Over the past decade, the principal investigator and her colleagues have incorporated neuroimaging into treatment studies to understand the neurobiology of geriatric depression. This strategy provides a unique opportunity to assess the functional integrity of neurochemical systems and the capacity of the brain to compensate for age and disease related (neurochemical and neuropathological) changes. These studies identified the functional neuroanatomy of geriatric depression and antidepressant treatment response with positron emission tomography (PET). Increased cortical glucose metabolism was observed in patients relative to controls. Decreased metabolism was observed in the same regions after antidepressant interventions and the decreases were correlated with improvement of mood and cognitive symptoms. Having identified the functional neuroanatomy, the next step is to examine the underlying pathophysiology. The proposed studies integrate recent advances in PET instrumentation and radiotracer chemistry, with postmortem and neuroimaging data, to investigate serotonin transporter (SERT) occupancy by a selective serotonin reuptake inhibitor (SSRI, citalopram) and beta-amyloid deposition. Greater SERT occupancy is correlated with greater improvement of mood symptoms, in regions that are hypermetabolic and are affected by citalopram treatment. The observation that cognitive impairment persists after mood symptom remission by SSRI treatment indicates that mechanisms other than serotonin dysfunction may underlie cognitive impairment. Beta-amyloid deposition may explain the metabolic alterations and persistent cognitive impairment. Beta-amyloid deposition is also observed in the regions that are hypermetabolic and is associated with episodic memory impairment in geriatric depression and normal aging (Butters et al., 2008, Sojkova et al., 2008). The specific aims of the revised application are: 1. to measure SERT availability in patients with geriatric depression and non-depressed, elderly controls and to measure SERT occupancy by citalopram in the patients and 2. to measure A deposition in patients with geriatric depression and non-depressed, elderly controls. The hypotheses will be tested that lower SERT availability, SERT occupancy by citalopram in the patients and greater A deposition will be observed in patients relative to controls will be observed in the same regions implicated in the glucose metabolism PET studies. The ultimate goal of the proposed studies is to obtain a mechanistic understanding of affective and cognitive symptoms to inform the development of more effective prevention and intervention strategies. Geriatric depression is a significant public health problem as it is associated with a dramatic increase in the rate of completed suicide and with greater mortality in the medically ill elderly. The prevalence of clinically significant depressive symptoms in community-residing elderly has been estimated from 8% to 16% and up to 50% in institutionalized and medically ill elderly. Even though there are effective antidepressant agents available, many patients are still refractory to treatment and demonstrate persistent cognitive impairment and cognitive decline, despite mood symptom improvement.